A Study Of Naxitamab , Granulocyte Macrophage Colony Stimulating Factor For Patients With Relapsed /Refractory , Soft Tissue or Anti GD2 Immunotherapy Refractory Neuroblastoma (NICE)

A Phase II Single Center Study Of Naxitamab , Granulocyte Macrophage Colony Stimulating Factor (GM CSF and Ifosfamide Carboplatin Etoposide) For Patients With Relapsed Refractory , Soft Tissue or Anti GD2 Immunotherapy Refractory Neuroblastoma

The purpose of this study is to evaluate safety and efficacy of naxitamab, granulocyte macrophage Colony Stimulating Factor (GM CSF) and Isofosfamide/Carboplatin/Etoposide (NICE) for Patients With Relapsed /Refractory, soft tissue or anti GD2 immunotherapy refractory Neuroblastoma

Study Overview

• Status: Completed
• Conditions: Refractory Neuroblastoma; Soft Tissue Cancer
• Intervention / Treatment: Drug: HITS; Drug: Naxitamab + GM-CSF cycles; Drug: NICE

Detailed Description

The anti-GD2 monoclonal antibody Naxitamab (also known as hu3F8) in combination with macrophage colony-stimulating factor (GM-CSF) is currently under pivotal phase 3 investigation for the treatment of High-Risk Neuroblastoma Patients with Primary or Secondary Refractory Osteomedullary Disease.

A subset of patients with high-risk, resistant disease, i.e., relapsed or refractory Neuroblastoma with soft tissue involvement as measured by 123I-Meta-iodobenzylguanidine (MIBG), 18F-FDG avid or measurable computed tomography (CT)/ magnetic resonance imaging (MRI) tumors outside of the bone marrow, or disease refractory to Naxitamab in combination with GM-CSF has shown significant response rates to a chemoimmunotherapy combination of Naxitamab, GM-CSF, irinotecan and temozolomide (HITS- Hu3F8, irinotecan, temozolomide and sargramostim) (NCT03189706). Treatment is administered on an outpatient basis and toxicities include those expected from I/T (myelosuppression and diarrhea) as well as pain and hypertension expected with Naxitamab. No other greater than grade 2 related toxicities occurred in this study (n=46). Early responses, assessed after 2 cycles, were documented in 18 (39%) patients and here complete (n = 9), partial (n = 8), and mixed (n = 1) and 13 patients had stable disease. Responses were achieved in refractory (3/7;43%) and progressive disease (15/39;38%) subgroups, in patients who had previously received I/T (12/34;35%) and/or anti-GD2 MoAb (14/36;39%), and in soft tissue (6/22; 27%) MIBG-avid skeletal sites (20/36;56%) and on bone marrow histology (9/12;75%). While encouraging, new strategies are warranted to further treat resistant disease.

A high-dose combination of ifosfamide, carboplatin, and etoposide (ICE) has activity against Neuroblastoma without cross-resistance to widely used chemotherapy regimens.

Through compassionate use, 4 patients with progression of disease or refractory disease after HITS therapy, have been further treated with two cycles of a combination of naxitamab, Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) and ifosfamide/Carboplatin/Etoposide (NICE). The first patient showed a complete response.

Toxicity included G2 prolonged aplasia and G3 hypertension, both expected from the chemotherapy agents and hu3F8. One patient progressed after the 2 cycles and the other 2 showed stable disease, according to the revised (2017) International Neuroblastoma Response Criteria (INRC).

In this formal trial, the investigators will investigate whether the combination of Naxitamab and GM-CSF with ifosfamide/Carboplatin/Etoposide (ICE) has a synergistic treatment effect in relapsed or refractory disease. The safety and efficacy of NICE (Naxitamab, Ifosfamide/Carboplatin/Etoposide) in patients that have not achieved complete remission with HITS chemo-immunotherapy will be assessed.

• Study Type: Interventional
• Enrollment (Actual): 47
• Phase: Phase 2

Contacts and Locations

Study Locations

• Spain
  • Barcelona
    • Esplugues De Llobregat, Barcelona, Spain, 08950
      • Hospital Sant Joan de Déu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Diagnosis of neuroblastoma (NB) as defined per INRC as

   1. histopathology of tumor biopsy, or
   2. BM aspirate or biopsy indicative of NB by histology plus high blood or urine catecholamine metabolite levels or MYCN amplification, or
   3. Fluorodeoxyglucose (FDG), MIBG avid lesion(s)

2. High-risk NB as defined as any of the following:

   1. Stage 4 with MYCN amplification
   2. Stage 4 without MYC amplification >1.5 y of age
   3. Stage 3 with MYCN amplification

3. Relapsed/refractory Neuroblastoma with

   1. Evidence of soft tissue disease or
   2. Progessive disease/incomplete response/relapsed to previous treatment with Naxitamab plus GM-CSF
4. Prior treatment with murine and hu3F8 is allowed
5. Prior treatment with irinotecan or temozolomide or ICE is permitted
6. Evaluable (microscopic marrow metastasis, elevated tumor markers, positive MIBG or PET scans) or measurable (CT, MRI) disease documented after completion of prior systemic therapy
7. Age ≥18 months

8. Acceptable hematological status defined as:

   1. Hemoglobin ≥8 g/dL (5.0 mmol/L)
   2. White blood cell count ≥1000/μL
   3. Absolute Neutrophil Count (ANC) ≥500/μL
   4. Platelet count ≥50,000/μL

9. Acceptable liver function defined as:

   1. alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤5 times Upper Limit of Normal (ULN)
   2. Bilirubin ≤1.5 x ULN

10. Acceptable kidney function defined as:

    a. estimated Glomerular Filtration Rate (eGFR) >60 mL/min/1.73 m2 calculated by the 2009 revised Bedside Schwartz Equation

11. Written informed consent from legal guardian(s) and/or patient in accordance with local regulations. Children must provide assent as required by local regulations (≥ 12 years old).

Exclusion Criteria:

1. Existing major organ dysfunction > grade 2, with the exception of hearing loss and hematologic toxicity (defined as suppression of all subtypes of WBCs, RBCs, and platelets).
2. Active life-threatening infection.
3. Pregnant women or women who are breast-feeding.
4. Inability to comply with protocol requirements, including genetic studies.
5. History of allergy to GM-CSF ≥ G4 (Common Terminology Criteria for Adverse Events- CTCAE) or does not respond to treatment.
6. Absolute Neutrophil Count (ANC) < 500/uL .
7. Platelet count <50,000/uL.
8. Patients with relapsed/refractory Neuroblastoma with solely bone marrow/bone involvement. Only patients with B/BM compartiment disease who show progressive disease/incomplete response/relapsed to previous treatment with Naxitamab plus GM-CSF may be eligible (inclusion critèrium #3).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Arm 1; Treatment involves 2 cycles of HITS: hu3F8, irinotecan, temozolomide, and GM-CSF. Irinotecan and temozolomide are given for 5 days, and hu3F8 and GM-CSF on specific days. Following this, 5 cycles of Naxitamab + GM-CSF are administered. Patients without a response receive NICE: hu3F8, GM-CSF, carboplatin, ifosfamide, and etoposide for 4 cycles. Patients with a complete response (CR) move to Naxitamab consolidation (5 cycles). This involves GM-CSF before and after, and hu3F8 on days 1, 3, and 5. Those with less than CR undergo 2 more NICE cycles, evaluated after the 4th. Lack of response leads to removal from the study.

Drug: HITS; Four doses of hu3F8, five doses each of irinotecan and temozolomide and five doses of GM-CSF. Irinotecan 50mg/m2/day IV will be administered from day 1-5concurrently with temozolomide 150mg/m2/day orally. Hu3F8 2.25mg/kg IV will be administered on days 2, 4, 9and11. GM-CSF 250mcg/m2/day SC will be administered on days 7-11; Drug: Naxitamab + GM-CSF cycles; Patients that achieve CR after 2 or 4 cycles of HITS will move on to 5 cycles of Naxitamab + GM-CSF cycles.; Drug: NICE; Patients that do not have an objective response (CR/PR) will receive NICE within 3 weeks from last dose. Each cycle of NICE consists of four doses of hu3F8, five doses of GM-CSF, one dose of carboplatin, and 3 doses each of ifosfamide and etoposide (table 2). Hu3F8 2.25mg/kg IV will be administered on days 2, 4, 9and 11. GM-CSF 250mcg/m2/day SC will be administered on days 7-11. Ifosfamide 1.5 gr/m2/day IV will be administered from day 1-3 concurrently with etoposide 100 mg/m2/day IV. Carboplatin 400 mg/m2/day IV will be administered on day 1

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with Serious and Non-Serious Adverse Events	The safety and tolerability of the treatment will be determined by means of type, incidence, severity, timing, seriousness, and relatedness of reported AEs, physical examinations, and laboratory tests. Toxicity will be graded and tabulated by the NCI CTCA E v 5 .0	14 months after ICF signature
Best Overall Response (at the end of HITS treatment)	Best Overall Response is defined as the best response recorded from the start of the study treatment	From first day of treatment with HITS until completion of HITS (39 days).
Best Overall Response of Complete Response (CR) (at the end of HITS treatment)	The number and proportion of patients with CR as Best Overall Response at the end of HITS treatment	From first day of treatment with HITS until completion of HITS(39 days).
Objective Response Rate (at the end of HITS treatment)	Objective Response Rate is defined as the proportion of patients with Best Overall Response of CR (complete response) or PR (partial response).	From first day of treatment with HITS until completion of HITS (39 days).
Clinical Benefit Rate (at the end of HITS treatment)	Clinical Benefit Rate is defined as the proportion of patients with Best Overall Response of CR (complete response) or PR (partial response) or SD (stable disease) ≥ 24 w	From first day of treatment with HITS until completion of HITS (39 days).
Best Overall Response (at the end of NICE treatment)	Best Overall Response is defined as the best response recorded from the start of the study treatment	From first day of treatment with NICE until completion of NICE (39 days).
Best Overall Response of Complete Response (CR) (at the end of NICE treatment)	The number and proportion of patients with CR as Best Overall Response at the end of NICE treatment	From first day of treatment with NICE until completion of NICE (39 days).
Objective Response Rate (at the end of NICE treatment)	Objective Response Rate is defined as the proportion of patients with Best Overall Response of CR (complete response) or PR (partial response).	From first day of treatment with NICE until completion of NICE (39 days).
Clinical Benefit Rate (at the end of NICE treatment)	Clinical Benefit Rate is defined as the proportion of patients with Best Overall Response of CR (complete response) or PR (partial response) or SD (stable disease) ≥ 24 w	From first day of treatment with NICE until completion of NICE (39 days).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To evaluate serum cytokines in patients receiving NICE		From first day of treatment with NICE, until day 11 post administration.
To measure MRD after HITS	Minimal residual disease for NB will be evaluated using the Revised International NB Response Criteria (JCO August 1, 2017)	From first day of treatment with HITS until completion of HITS (39 days).
To measure MRD after NICE	Minimal residual disease for NB will be evaluated using the Revised International NB Response Criteria (JCO August 1, 2017)	From first day of treatment with NICE until completion of NICE (39 days).

Collaborators and Investigators

• Sponsor: Fundació Sant Joan de Déu

Study record dates

Study Major Dates

• Study Start (Actual): August 20, 2020
• Primary Completion (Actual): July 20, 2023
• Study Completion (Actual): October 24, 2023

Study Registration Dates

• First Submitted: March 21, 2024
• First Submitted That Met QC Criteria: May 30, 2024
• First Posted (Actual): June 3, 2024

Study Record Updates

• Last Update Posted (Actual): August 29, 2024
• Last Update Submitted That Met QC Criteria: August 27, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroectodermal Tumors, Primitive; Neuroectodermal Tumors, Primitive, Peripheral; Sarcoma; Neuroblastoma
• Other Study ID Numbers: HSJD HR NB.2 2019

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes